PLAC8, a protein that until now has been poorly understood, appears to play a key role in the spread - or metastasis - of colorectal or colon cancer.
Previous research has already found that PLAC8 is linked to colon cancer. Now, in a new study published in the Journal of Clinical Investigation, researchers from Washington University School of Medicine in St. Louis, MO, and Vanderbilt University Medical Center in Nashville, TN, reveal that the protein triggers normal cells lining the colon to change into a state that helps colon cancer to spread.
Co-author Lilianna Solnica-Krezel, professor and head of Washington's Department of Developmental Biology, says:
"We knew levels of this protein are elevated in colon cancer. Now we've shown what PLAC8 could be doing - causing the cells to transition to a state that allows them to spread."
The research, which involves studying the protein in zebrafish, started at a lab in Vanderbilt University and then moved to Washington University.
Vanderbilt is also where senior author Robert Coffey, the Ingram Professor of Cancer Research, and his group have been developing ways of growing colon cancer cells in three dimensions instead of the more conventional two-dimensional flat dish culture.
When they managed to get the colon cancer cells to grow in three dimensions, the group found they grew into one of two shapes: either hollow balls or spiky clumps with the spiky bits protruding into their surroundings.
Then, upon injecting these two types of colon cancer cells into mice, they found the spiky clumps formed tumors that spread more rapidly.
Too much PLAC8 causes zebrafish embryos to develop abnormally
When the team compared the genetic signatures of the two types of three-dimensional cancer cells, they found the spiky clumps, which formed the more aggressive tumors, had very much higher levels of expression of PLAC8.
This is where the zebrafish come in. They are an ideal lab model - for instance they are versatile, small and easy to breed - for studying many of the biological processes that are common across vertebrate species. In this case, the team used them to study PLAC8 to see exactly how it influences different types of tissue and cells, as Prof. Solnica-Krezel explains:
"We looked at this protein in zebrafish and saw that it was also expressed in the gut. In normal zebrafish, PLAC8 is present on the inner lining of the gut. We also noticed PLAC8 is heavily expressed in the early embryos of zebrafish."
The team also found that when there is too much PLAC8, the zebrafish embryos develop abnormally - the cells move more slowly resulting in abnormal body shapes and other defects.
Too much PLAC8 appears to have similar effects as mutated E-cadherin
The researchers found that PLAC8 spurred normal cells in the colon lining to help spread colon cancer.
The researchers noticed that the growth defects caused by too much PLAC8 are similar to those that arise when the protein and cell-adhesion molecule E-cadherin is mutated.
E-cadherin sits on cell surfaces and helps them stick to one another. The amount of protein is critical for cell movement - too much or too little has a bad effect on cell mobility.
E-cadherin is also important for the maintenance of the epithelium, a sheet-like tissue that forms the lining of organs, including the gut. If there is not enough of the protein, the epithelium begins to transform into another tissue called mesenchyme, where cells are more loosely associated and surrounded by a large extracellular matrix.
During this epithelial-to-mesenchymal transition, the gut loses its sheet-like structure, allowing cells to migrate more easily.
Some of these transitions are a normal part of early development where cells have to be able to travel to different parts of the developing organism and develop into new tissue and organs.
However, this is not what you want in cancer - tumor cells being able to travel easily to other parts of the body and set up new sites and grow there.
E-cadherin's influence on these transitions is well studied, says Prof. Solnica-Krezel. But this study is the first to suggest that PLAC8 could be regulating E-cadherin: "Too much PLAC8 causes E-cadherin levels to go down, and low E-cadherin is associated with abnormal cell movement," she explains.
Researchers found similar markers of excess PLAC8 in human colon cancer tumors
In the final part of the study, the team went back to human tissue and looked at what PLAC8 does to colon tumors. They found many of the molecular features they observed in the epithelial-to-mesenchymal transitions when there was too much PLAC8 in the zebrafish embryos were also to be found on the edges of human colorectal tumors.
They suggest PLAC8 could be a new target for cancer drugs, for instance that block its effect.
But for now, Prof. Solnica-Krezel says that the study's main value will be in helping prognosis: tumors with high levels of PLAC8 are likely to be the most aggressive.
The study was sponsored by the National Institutes of Health (NIH).
Medical News Today recently learned how gut microbes may play a role in colorectal cancer. Writing in the Journal of Experimental Medicine, researchers in the US suggest that a person's particular mix of gut microbes influences the development of colorectal cancer tumors by interacting with genes and inflammatory responses.